The role of lysophosphatidic acid (LPA) in immune regulation is rapidly being elucidated. This pleiotropic lipid mediator is now known to regulate many aspects of immune responses, with recent studies indicating a role in regulating cell homing. Growing evidence indicates that LPA contributes to the pathogenesis of asthma. We recently reported that lysophosphatidic acid is constitutively present in bronchoalveolar lavage (BAL) fluids but significantly increased after segmental allergen challenge of allergic human subjects. Extracellular LPA is thought to be generated by hydrolysis of lysophosphatidylcholine by the enzyme autotaxin (ATX), but very little is known about ATX expression or LPA generation in the lung. LPA can bind and activate different G-protein coupled receptors, including the classical receptors LPA1, LPA2 and LPA3. Our proposal is based on two fundamentally new observations, namely that: (i) LPA plays a previously unsuspected role in the initiation of immune responses, and (ii) LPA2 appears to be a previously underappreciated negative regulatory receptor in mouse models of allergic lung inflammation. Here we will build on these findings and characterize ATX expression and LPA generation in the lung using novel assays of enzyme activity and quantitative mass spectrometry (Aim 1a), use loss-of-function and gain-of-function approaches to manipulate ATX expression in vivo (Aim 1b), explore the role of other LPA receptors in mouse models of allergic airway inflammation using new receptor antagonists (Aim 2), and determine the precise mechanisms by LPA2 inhibits allergic immune responses using complementary approaches to dissect the contributions of lung structural cells, dendritic cells, and CD4+ T lymphocytes (Aim 3). Taken together, these studies will allow us to construct new and definitive models of LPA generation and action in the lung, and should lay the groundwork for novel future therapies in asthma. PUBLIC HEALTH RELEVANCE: Asthma is a chronic disease that affects millions of Americans, and is a common cause of lost days from school and work. Despite the availability of effective therapies, asthma is not a curable disease and asthmatic patients must learn to live with and manage their symptoms. Asthma is now known to be caused by airway inflammation. The goal of our research program is to define the role of new molecules that cause lung inflammation in asthma with the hope that this will lead to the use of new therapeutic agents in this disease.